The invention relates to a novel process for preparing 4-(4xe2x80x2-carboxyphenyl)-pyridine of the formula (I). 
4-(4xe2x80x2-Carboxyphenyl)pyridine of the formula (I) and the corresponding esters and acid chlorides are important intermediates in the synthesis of active compounds for the pharmaceutical and agrochemical industries.
Possible synthetic routes to compounds of the formula (I) are the Suzuki coupling of 4-halopyridines with suitable organometallic reagents, for example 4-carboxyphenylboronic acid or 4-carboxyphenylboronic esters. However, such pyridines, for example, 4-bromopyridine or 4-chloropyridine, are firstly very expensive and difficult-to-obtain raw materials which are also unstable in pure form and can be used only in the form of derivatives, for example as hydrochloride. Secondly, they are very corrosive and place high demands on the materials of construction used.
It is an object of the present invention to develop a process for preparing 4-(4xe2x80x2-carboxyphenyl)pyridine of the formula (I) which makes it possible to obtain the target compound in very few, technically simple steps starting from readily available and inexpensive raw materials. Furthermore, the process to be developed has to give the target product in a good total yield and in a purity sufficient for pharmaceutical applications.
It has surprisingly been found that the compound of the formula (I) can be prepared in good total yields and in good purity in few steps starting from pyridine. The individual steps can each be carried out in a technically simple manner and use only commercially available and inexpensive reagents, solvents and catalysts.
The present invention provides a process for preparing 4-(4xe2x80x2-carboxyphenyl)pyridine, which comprises oxidizing a 4-phenyl-N-acyldihydropyridine of the formula (II) 
where
R1 is a bulky alkyl, alkylaryl, arylalkyl or alkoxy group and
R2 is a straight-chain or branched, substituted or unsubstituted alkyl radical having from 1 to 8 carbon atoms,
by means of an oxidizing agent selected from the group consisting of permanganates, nitric acid, Cr(VI) compounds, oxygen and air to give the compound of the formula (I) 
where M is a cation, preferably hydrogen, ammonium or an alkali metal cation.
Preferred radicals R1 are tert-butyl, isopropyl, (dimethyl)phenylmethyl, methyl(diphenyl)methyl, trityl, diphenylmethyl, triethylmethyl, tert-butoxy and isopropoxy.
Preferred radicals R2 are straight-chain or branched alkyl radicals which have from 1 to 4 carbon atoms and may be unsubstituted or substituted by one or more hydroxy or C1-C4-alkoxy radicals; particular preference is given to methyl, ethyl, n-propyl, i-propyl, n-butyl, methoxymethyl and hydroxymethyl, most preferably methyl.
The preparation of dihydropyridines of the formula (II) from pyridine by addition of organometallic compounds, for example Grignard compounds, cannot be carried out directly; prior activation of the pyridine ring is necessary. This can be achieved, for example, by N-acylation (Scheme 1). The N-acylpyridinium salts which can be obtained in this way do react with Grignard compounds, but the reaction gives mixtures of 2- and 4-aryldihydropyridines which are difficult to separate. According to Akiba et al., Tetrahedron Lett. 23, 4, 429-432, 1982, a high selectivity to the 4-aryldihydropyridines can be achieved by using bulky radicals on the pyridine nitrogen and using equimolar amounts of organocopper compounds. However, for a number of reasons, the preparation and handling of organocopper compounds is problematical for industrial processes. 
X can be Cl or Br.
The problem is solved more elegantly by Comins et al., J. Org. Chem. 1982, 47, 4315-4319. The authors react Grignard compounds with pyridine and pivaloyl chloride in the presence of catalytic amounts of CuI and obtain yields of somewhat above 60% in this way. The amounts of Cu required do not stand in the way of industrial utilization. However, such a low yield combined with the disposal problems associated with the sometimes problematical by-products resulting from the starting materials not converted into product makes the viability of the overall process questionable.
It has surprisingly been found that the addition of palladium or nickel salts or complexes or of metallic Pd or Ni as cocatalysts leads to a significant increase in yield in the preparation of a dihydropyridine of the formula (II). Yields of usually above 90%, based on the organometallic reagent used, are then achieved.
In a preferred embodiment of the process of the invention, the compound of the formula (II) is therefore prepared by acylating pyridine by means of a compound of the formula (IV) to give a compound of the formula (VI), or using a compound of the formula (VI), and coupling the compound of the formula (VI) with a Grignard compound of the formula (V) in the presence of from 0.01 to 10 mol %, preferably from 0.1 to 5 mol %, based on the Grignard compound, of a Cu compound, and in the presence of a Pd or Ni cocatalyst, 
where X is Cl or Br.
Suitable solvents for the coupling of the compound of the formula (IV) with (V) are, for example, aliphatic or aromatic ethers or hydrocarbons, preferably THF or THF/toluene mixtures. The coupling can be carried out at temperatures in the range from xe2x88x9280xc2x0 C. to the boiling point of the solvent used. However, the proportion of the 2-substitution product increases at the expense of the desired 4-substitution product at high temperatures, so that temperatures of from xe2x88x9270 to +60xc2x0 C. are preferred. Particular preference is given to temperatures of from xe2x88x9250 to +50xc2x0 C., particularly preferably from xe2x88x9235 to +40xc2x0 C. Suitable Cu compounds are Cu(I) and Cu(II) compounds, preferably CuI, CuBr, CuCl or CUCl2.
Suitable cocatalysts for the coupling reactions are salts, complexes or the metallic form of nickel or palladium. The amounts employed can be from 10xe2x88x925 to 10 mol %, preferably from 10xe2x88x924 to 7.5 mol %, in particular from 10-3 to 5 mol %, based on the Grignard compound.
Particular preference is given to salts or complexes of nickel or palladium and also metallic forms, if desired on a suitable support, e.g. Pd on C or on BaSO4, very particularly preferably PdCl2(dppf), PdCl2(PPh3)2, PdCl2(dppe), PdCl2(dppp), PdCl2(dppb), Pd(PPh3)4, Pd(OAc)2, PdCl2, PdBr2 or NiCl2(PPh3)2, where xe2x80x9cdppfxe2x80x9d is 1,2-bis(diphenylphosphino)ferrocene, xe2x80x9cdppexe2x80x9d is 1,2-bis(diphenylphosphino)ethane, xe2x80x9cdpppxe2x80x9d is 1,2-bis(diphenylphosphino)propane, xe2x80x9cdppbxe2x80x9d is 1,2-bis(diphenylphosphino)butane, xe2x80x9cPhxe2x80x9d is phenyl and xe2x80x9cAcxe2x80x9d is acetyl.
The conversion of the dihydropyridine of the formula (II) into 4-(4xe2x80x2-carboxyphenyl)-pyridine of the formula (I) is achieved according to the invention by oxidation using an oxidizing agent selected from the group consisting of permanganates, e.g. sodium or potassium permanganate, nitric acid, chromium(VI) reagents, e.g. alkali metal chromates or alkali metal dichromates, oxygen and air, particularly preferably by air oxidation.
According to Comins et al., it is possible to convert N-acylated 4-aryldihydropyridines into the corresponding 4-arylpyridines by heating with elemental sulfur.
However, large amounts of hydrogen sulfide and other sulfur compounds are formed in the treatment with sulfur and, furthermore, high temperatures are required, resulting in a very impure, black product. This is very cumbersome to purify to the extent required for further oxidation.
It has surprisingly been found that the dihydropyridine of the formula (II) can be oxidized in a single step to give a very pure product of the formula (I). Despite the successive oxidations of the N-acyl group, of the dihydropyridine to give the pyridine and of the aromatic alkyl group to give the acid group, good yields of a pure product are obtained.
The oxidation can be carried out by means of permanganates, nitric acid, air, O2, or chromium(VI) reagents; however, oxidation by means of air has been found to be particularly advantageous. Almost quantitative yields and a high purity are obtained in this way. Small amounts of the only detectable impurity, namely terephthalic acid, can be easily and quantitatively removed by washing with dilute alkalis.
The oxidation by means of permanganate can be carried out either in aqueous solution or in a nonaqueous medium, preferably at temperatures of from 0 to 100xc2x0 C., in particular from 10 to 80xc2x0 C. In aqueous solution, the presence of suitable phase transfer catalysts, for example tetraalkylammonium salts, tetraphenylphosphonium salts or crown ethers, is necessary to achieve good yields. The work-up is carried out by filtering off the manganese dioxide formed, acidifying the filtrate and filtering off the pyridylbenzoic acid which precipitates.
The oxidation using air or oxygen is carried out in aliphatic carboxylic acids, if desired in admixture with water. Preference is given to using acetic acid, particularly preferably a mixture of acetic acid and water. Heavy metal salts, e.g. mixtures of cobalt bromide and manganese bromide, are employed as catalysts. The heavy metal salts are used in amounts of from 0.01 to 5.0 mol % each, preferably from 0.1 to 4.0 mol % each, particularly preferably from 1.0 to 2.0 mol % each, based on the dihydropyridine (II). The ratio of cobalt to manganese can be varied within wide limits and can be, for example, from 1:5 to 5:1. The two salts are preferably used in equimolar amounts. The reaction is carried out at temperatures of from 100 to 200xc2x0 C., preferably from 120 to 180xc2x0 C. and particularly preferably from 150 to 170xc2x0 C. The pressure is in the range from atmospheric pressure to 50 bar. The work-up is carried out by cooling and, if appropriate, concentrating the reaction mixture by evaporation, then filtering off, washing and drying the resulting precipitated carboxylic acid.